The transient hypofunction of NMDARs during early postnatal development modifies the paired-pulse ratio at the LPP and the MPP synapses.
Consistent with previous studies (Petersen et al., 2013; Collitti-Klausnitzer et al., 2021), the PPF (60 ms inter-stimulus interval, ISI) differs between the LPP and MPP synapses. We corroborated that the LPP has a prominent PPF (PPF at the LPP – DG = 1.72 ± 0.03;n = 28 slices / 15 animals) compared to the MPP (PPF at the MPP – DG = 1.22 ± 0.03; n = 29 slices / 15 animals; Student’s t-test: t(55) = 12.01, P < 0.001). Figure 2a shows the PPF distribution of the LPP and the MPP using a violin graph and the responses obtained from 57 independent dorsal hippocampal slices. Figure 2b shows representative examples of facilitation from the LPP and the MPP and their corresponding depression in response to selective activation of group III and II mGluRs, respectively. Because neonatal treatment with MK-801 enhances the PPF at the Mossy Fiber – CA3 pyramidal cell synapse of the rat hippocampus (Segev et al., 2020; Márquez et al., 2023), we performed a similar exploration on the LPP and the MPP using a broader ISI range (40, 60, 100, 200, and 500 ms). The exploration of the LPP PPF revealed increased facilitation in the MK-801 slices compared to control slices (two-way RM ANOVA, treatment effect: F(1, 16) = 5.19, P< 0.05; n = 9 slices / 7 animals, for each condition, Figure 2c). The LPP PPF level was statistically increased at 40 and 60 ms (LPP PPF at 40 ms in control: 1.64 ± 0.07; in MK-801: 2.01± 0.01; t(16) = 2.57, P < 0.05; at 60 ms: 1.74 ± 0.06; in MK-801: 1.99 ± 0.06; t(16) = 2.9, P< 0.01; at 100 ms: 1.71 ± 0.02; in MK-801: 1.79 ± 0.04; t(16) = 1.5, P > 0.05). The temporal change in the PPF is depicted in the representative traces of Figure 2d.
The MPP PPF also showed increased facilitation in the MK-801-treated slices (n = 9 slices / 7 animals) compared to control slices (n = 8 slices / 6 animals; two-way RM ANOVA, treatment effect: F(1, 15) = 4.63, P < 0.05; Figure 2e). The facilitation was limited to the ISI of 200 ms (PPF at 60 ms in control: 1.32 ± 0.06; in MK-801: 1.52 ± 0.08; t(15) = 1.854,P > 0.05; at 100 ms: 1.3 ± 0.06; in MK-801: 1.51 ± 0.09; t(15) = 1.77, P < 0.05; at 200 ms: 1.16 ± 0.05; in MK-801: 1.36 ± 0.04; t(15) = 2.95,P < 0.01; representative traces in Figure 2f). The increased PPF observed in the LPP and the MPP synapses suggests a dysregulation in the presynaptic machinery that controls glutamate release on the DG granule cells.